REPLIDERM Inc. REPLIDERM Inc. GROUP 8 Tiwalade Ashaye, Joseph Azzarello, Ben Fairbanks, Mitch Hargis, Krupa Patel, Holap Tang
OVERVIEW OVERVIEW � Background/Review of current conditions � Objective of RepliDerm � Production plan � FDA Approval Process � Business/Market Plan
BACKGROUND BACKGROUND
Problem Problem � 270,000 burn victims per year in the U.S. requiring hospitalization � 1.5 million diabetic patients in the U.S. with wound ulcers � Various narcotizing infections (flesh eating infections)
Treatments Available Treatments Available � Split thickness autograft � Donor allograft � Synthetic allograft � Synthetic allograft with seeded neo- natal fibroblasts � Temporary covering from biological donor
Advantages of Existing Advantages of Existing Treatments Treatments Procedure Advantages Disadvantages Price/in 2 (Product) Split Thickness Autograft Inexpensive Extensive scarring $0 (Surgical treatment) No rejection Limited donor sites Donor Allograft Relatively Disease transmission $7/in 2 (AlloDerm) Inexpensive 10% Rejection Small wounds only Synthetic Allograft with No epidermal graft Fragile $102/in 2 Seeded Cells needed (Epicel) 5% Rejection Synthetic (Integra) Strong & supple Epidermal autograft $42/in 2 Protective layer required 5% Rejection
On the Market: Integra Dermal On the Market: Integra Dermal Regeneration Template Regeneration Template
On the Market: Integra Dermal On the Market: Integra Dermal Regeneration Template Regeneration Template
Mechanism for Angiogenesis Mechanism for Angiogenesis
On the Market: Integra Dermal On the Market: Integra Dermal Regeneration Template Regeneration Template
On the Market: Integra Dermal On the Market: Integra Dermal Regeneration Template Regeneration Template
On the Market: Integra Dermal Regeneration Template
Product Objective Product Objective � To produce a synthetic dermal replacement template that increases the speed of vascularization and quality of burn and wound treatment.
Growth Factors Growth Factors � Basic Fibroblast Growth Factor- BFGF � Acidic Fibroblast Growth Factor- AFGF � Platelets Derived Growth Factor- PDGF � Vascular Endothelial Growth Factor- VEGF
VEGF Stimulation of Angiogenesis VEGF VEGFR2 PLC γ 1 PI3 kinase Morphogenesis Cell Proliferation
Methods of Delivery � Daily Injections � VEGF in the crosslinked collagen matrix � VEGF in suspension in pores of matrix � Controlled release microparticles
Controlled Release particles Controlled Release particles � Optimize rate of vascularization by altering: – Number/VEGF Concentration of Microcapsules – Location of Microcapsules – Size of Microcapsules
Microcapsule Diffusion Model Microcapsule Diffusion Model � A model of the VEGF’s motion through the implant could be created and used to create a more-effective product � If a model with predictive capabilities was created, then the ideal initial concentration and placement of the microbeads could be determined
Microcapsule Diffusion Model Z=+L � No flux across top layer: ( δ c/ δ z = Region #1 0 @ z=L) � Bottom layer rises with time as Z=0 Layer containing Microbeads (#2) tissue vascularizes into graft � Living tissue carries away VEGF Region #3 Z=y(t) with a rate k v f(c 3 ) Z=-L at y(0) � Regions 1,2, and 3 have a Living Tissue (Region #4) diffusion coefficient D 1 � Region #4 has diffusion coefficient D 2 Microbead region releases VEGF with � Molar fluxes are equal at region rate r* and at a concentration c* interfaces
Microcapsule Diffusion Model Microcapsule Diffusion Model � With the model described in the previous slide, the following expression is obtained: 2 − k r * y dy g α = t e 3 dt k � y(t) (the “rate of healing”) can be approximated from the above model
PRODUCTION PROCESS PRODUCTION PROCESS
REPLIDERM PRODUCTION REPLIDERM PRODUCTION � Raw material needed � Equipments needed � Description of process � Human labor needed � Facility layout
REPLIDERM Production REPLIDERM Production � Raw materials needed � Equipments needed � Description of process � Human labor needed � Facility layout
REPLIDERM Production REPLIDERM Production (Raw materials) (Raw materials) Procedure Description Use (Product) Bovine Extracellular protein Support and structure of matirx Collagen Chondroitin Glycoproteins known as forms the ground substance in 6-Sulfate proteoglycans found in the extracellular matrix of shark cartilage connective tissue. Silastic Silicon layer Used as a temporary barrier to protect against infection PLGA( polylactic Biodegradable, Manufacture of microspheres glycolic acid biocompatible polyester PEG Polymer Speeds up degradation of the ( Polyethylene- microbeads. It also forms the glycol ) sphere shape of the beads VEGF As described earlier A protein growth factor
REPLIDERM Production REPLIDERM Production � Raw material needed � Equipments needed � Description of Process � Human labor needed � Facility layout
Repliderm Production (Equipments Needed) � Small Equipment � Batch processes Tissue Homogenizer Blender Centrifuge Vortex Vacuum oven
REPLIDERM Production REPLIDERM Production � Raw material needed � Equipments needed � Description of Process � Human labor needed � Facility layout
Before Microbead addition… … Before Microbead addition
After Microbead addition… … After Microbead addition
Microcapsule Production Microcapsule Production � Raw materials - • PLGA Poly(lactic-co-glycolic) acid (50:50) • PEG (Polyethylene- glycol) • VEGF (Vascular endothelial growth factor) • Albumin • PVA (polyvinyl alcohol) • Isopropanol
MICROCAPSULE PRODUCTION
REPLIDERM Production REPLIDERM Production � Human Labor Needed – Minimum – 1PhD, 3 technical assistants � Facility Layout (30,000sq-ft) – 1 cryo room, Storage, Offices, Animal storage, Laboratory testing, 2 Production rooms
Quality Control • 1% of all sheets produced to be selected at random and tested for quality assurances – All of sheets to be tested are halved. Half of each sheet are tested on a chorioallantoic membrane. – The remaining halves are tested in vitro with vascular endothelial cells
FDA PROCESS FDA PROCESS
FDA Approval Process • Most costly and time consuming step in bringing a new product to market. � REPLIDERM is a Class III medical device. Class III medical devices are those that are implanted into a patient and left in the body. � Non-clinical testing � Manufacturing and facility testing � Clinical testing
FDA Approval Process • Modular Pre-Market Approval Process • Module 1: Non-clinical Trials • Module 2: Manufacturing & Facility Testing • Module 3: Human Clinical Trials
FDA Testing � Historically FDA testing requires $200,000,000 to $300,000,000 and can last 10-15 years. � It is this cost and time delay the FDA testing is the most critical step in bringing a new product to the market.
First Stage Variables � A 1 st Stage Variable is a decision that must be made before any production begins. � For our project, we have two 1 st Stage Variables: – The number of personnel to hire – The number of experiments to run before submitting our product to FDA evaluation.
Second Stage Variables � A 2 nd Stage Variable is a decision that is made after an outcome. � For our project, we have several 2 nd Stage Variables: – Each 2 nd Stage Variable is a choice on whether or not to continue after an FDA Failure. – The chance of having an FDA Failure is dependent on the amount of tests conducted prior to FDA review.
First Stage Variable � Number of Personnel Options: – 1 Ph.D. and 3 Lab Technicians – 1 Ph.D. and 5 Lab Technicians – 1 Ph.D. and 7 Lab Technicians � Number of Experiments to Run Prior to submission to FDA review: Set Cell CAM Nude Guinea Pigs Dogs Tests Tests Mice Pigs A 100 100 100 100 100 100 B 100 100 50 50 50 50 C 50 50 50 50 25 25
Second Decision (First Stage Variable) Set Description Description Set A 100 Cell Flask, 100 CAM, More time and money spent up 100 Nude Mice, 100 front, but higher likelihood of passing FDA trials on 1 st try. Guinea Pig, 100 Pig, 100 Dog Tests Set B 100 Cell Flask, 100 CAM, Compromise on time and 50 Nude Mice, 50 Guinea money, but the chances of Pig, 50 Pig, 50 Dog Tests passing FDA are less than A. Set C 50 Cell Flask, 50 CAM, Lest costly, but higher 50 Nude Mice, 50 Guinea likelihood of being forced to Pig, 25 Pig, 25 Dog Tests repeat some FDA trials.
Initial Grant Money � The initial amount of grant money that we obtain will be the deciding factor in which employment option and which testing option we choose. � Initial grant money will be obtained from the NIH, NSF, CDC, and other various government granting agencies.
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